Purpose: Uterine-serous-carcinoma (USC) is a rare and aggressive variant of endometrial cancer. Whole-exome-sequencing (WES) studies have recently reported c-Myc gene amplification in large number of USC suggesting c-Myc as a potential therapeutic target. We investigated the activity of novel BET bromodomain inhibitors (GS-5829 and GS-626510, Gilead-Science-Inc.) and JQ1 against primary USC-cultures and USC-xenografts. Experimental Design: We evaluated c-Myc expression by qRT-PCR in a total of 45 USC including fresh-frozen-tumor-tissues and primary USC-cell-lines. We also performed immunohistochemistry (IHC) and Western-Blot experiments in 8 USC tumors. USC cultures were evaluated for sensitivity to GS-5829, GS-626510 and JQ1 in-vitro using proliferation, viability and apoptosis-assays. Finally, the in-vivo activity of GS-5829, GS-626510 and JQ1 was studied in USC-ARK1 and USC-ARK2 mouse-xenografts. Results: Fresh-frozen USC and primary USC cell-lines overexpressed c-Myc when compared to normal tissues (p =0.0009 and =0.0083, respectively). High c-Myc expression was found in 7 of 8 of primary USC cell lines tested by qRT-PCR and 5 of 8 tested by IHC. In-vitro experiments demonstrated high sensitivity of USC cell-lines to the exposure to GS-5829, GS-626510 and JQ1 with BET-inhibitors causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis). In comparative in-vivo experiments GS-5829 and/or GS-626510 were found more effective than JQ1 at the concentrations/doses used in decreasing tumor-growth in both USC-ARK1 and USC-ARK2 mouse-xenograft-models. Conclusions: GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy resistant USC overexpressing c-Myc. Clinical studies with GS-5829 in USC-patients harboring chemotherapy-resistant disease are warranted.
https://ift.tt/2Kly2Oo
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου
Σημείωση: Μόνο ένα μέλος αυτού του ιστολογίου μπορεί να αναρτήσει σχόλιο.